Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• the present invention relates to the use of triazoloquinazolines for the treatment of central nervous disorders.
• Triazoloquinazolines have been disclosed in EP-A 80 176. These compounds are reported to have an anti-allergic effect. It is furthermore known that certain pyrazoloquinazolines are suitable inter alia for the treatment of neurological disturbances (US-A 5 153 196).
• the invention relates to the use of compounds of the formula I ##STR2## where X is carboxyl, where appropriate in the form of its salt with a physiologically tolerated amine cation or metal cation; the radical ##STR3## where R 4 is C 1-8 -alkyl, cycloalkyl with 3 to 8 carbons in the ring, benzyl, one of the radicals ##STR4## where n is 2, 3 or 4 and R 5 and R 6 are each C 1-3 -alkyl; hydroxy-C 1-4 -alkyl, nitrile-C 1-4 -alkyl, tetrazolyl, carbonylaminotetrazole or carbamoyl, and
• R 1 and R 2 which are identical or different, and [sic] are hydrogen, fluorine, chlorine or bromine atoms, trifluoromethyl, nitro, amino, C 1-5 -alkyl, mono- or di-C 1-5 -alkylamino groups, a C 1-6 -alkoxy group, a C 1-6 -alkylthio, C 1-6 -alkylsulfenyl, C 1-6 -alkylsulfonyl, di-C 1-6 -alkylaminosulfonyl radical, or
• R 1 and R 2 together form a methylene- or ethylenedioxy group or a C 3-5 -alkylene group
• Examples of relevant central nervous disorders are epilepsy, brain damage, Parkinson's disease, Alzheimer's disease, emesis, and trauma of the head and spinal cord.
• the compounds of the formula I have the further advantage that they have spasmolytic, antiepileptic, anxiolytic and antidepressant properties.
• the effect of the compounds derives from their glutamate-antagonistic properties.
• the pharmacological activity of the compounds I according to the invention was investigated on isolated membrane material from rat cerebra.
• the membrane material was treated in the presence of the compounds according to the invention with the radiolabeled substances 3 H-2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ( 3 H-AMPA) and 3 H-5,7-dichlorokynurenic acid, these binding to specific receptors (AMPA and NMDA (N-methyl-D-aspartate) receptors respectively).
• AMPA and NMDA N-methyl-D-aspartate
• rat cerebra were homogenized together with 15 times the volume of a buffer solution A composed of 30 mM ⁇ , ⁇ , ⁇ -tris(hydroxymethyl)methylamine hydrochloride (TRIS-HCl) and 0.5 mM ethylenediaminetetraacetic acid (EDTA), pH 7.4, using an Ultra-Turrax.
• the suspension was centrifuged at 4,000 g for 20 minutes. After removal of the supernatant liquid, the proteinacious membrane material contained in the sediment was washed three times by suspending it in buffer solution A and subsequently centrifuging at 48,000 g for 20 minutes each time.
• the membrane material was then suspended in 15 times the volume of buffer solution A and incubated at 37° C. for 30 minutes. The protein material was subsequently washed twice by centrifugation and suspension and stored at -70° C. until used.
• the protein material was thawed at 37° C. and washed twice by centrifuging at 48,000 g (20 minutes) and subsequently suspending in a buffer solution B composed of 50 mM TRIS-HCl, 0.1M potassium thiocyanate and 2.5 mM calcium chloride, pH 7.1. Subsequently 0.25 mg of membrane material, 0.1 ⁇ Ci of 3 H-AMPA (60 Ci/mmol) and compound I were dissolved in 1 ml of buffer solution B and incubated on ice for 60 minutes. The incubated solution was filtered through a CF/B filter (from Whatman) which had previously been treated for at least 2 hours with a 0.5% strength aqueous solution of polyethyleneimine.
• a buffer solution B composed of 50 mM TRIS-HCl, 0.1M potassium thiocyanate and 2.5 mM calcium chloride, pH 7.1.
• 0.25 mg of membrane material, 0.1 ⁇ Ci of 3 H-AMPA (60 Ci/mmol) and compound I
• the filtrate was subsequently washed with 5 ml of cold buffer solution B in order to separate bound and free 3 H-AMPA from one another.
• the radioactivity of the bound 3 H-AMPA in the membrane material was measured by scintillation counting and then the K I was determined by subjecting the displacement plots to regression analysis.
• rat cerebra were homogenized together with about 10 times the volume of a buffer solution A composed of 50 mM TRIS-HCl and 10 mM EDTA, pH 7.4.
• the suspension was centrifuged at 48,000 g for 20 minutes. After removal of the supernatant liquid, the membrane material contained in the sediment was washed twice by suspending it in buffer solution A and subsequently centrifuging for 20 minutes each time. After resuspension of the membranes in buffer solution A and freezing in liquid nitrogen, the suspension was thawed again at 37° C. and, after another wash, incubated at 37° C. for 15 minutes. The protein material was subsequently washed four times by centrifugation and suspension and stored at -70° C. until used.
• the protein material was thawed at 37° C. and washed twice by centrifuging at 48,000 g (20 minutes) and subsequently suspending in a buffer solution B composed of 50 mM TRIS-HCl, pH 7.4. Subsequently 0.15 mg of membrane material, 0.3 ⁇ Ci 3 H-5,7-dichlorokynurenic acid (16 Ci/mmol) and compound I were dissolved in 1 ml of buffer solution B and incubated on ice for 30 minutes. The incubated solution was centrifuged at 150,000 g for 2 minutes. After removal of the supernatant liquid, the sediments were suspended twice using 1.5 ml of cold buffer solution B each time. The radioactivity of the 3 H-5,7-dichlorokynurenic acid bound to the membranes in the sediment was measured, and the K I was obtained by subjecting the displacement plots to regression analysis.
• the compounds I are suitable as active substances in drugs for human and veterinary medicine.
• the drug formulations contain a therapeutically effective amount of compound I in addition to conventional pharmaceutical ancillary substances.
• the drug formulations can be administered in various ways such as orally, parenterally, subcutaneously, intraperitoneally and topically.
• possible presentations are tablets, emulsions, solutions for infusion and injection, pastes, ointments, gels, creams, lotions, dusting powders and sprays.
• the active substances can be present in the conventional concentrations.
• the content of active substances is, as a rule, from 0.001 to 5% by weight, preferably from 0.01 to 0.5% by weight.
• the preparations are administered in single doses. From 0.1 to 50 mg, preferably from 0.1 to 10 mg, of active substance are given in a single dose per kg of body weight.
• the formulations can be administered in one or more dosages each day depending on the nature and severity of the disorder.
• the daily dose is, as a rule, from 0.1 to 100 mg per kg of body weight on oral administration and from 0.01 to 10 mg per kg of body weight on parenteral administration.
• the drug formulations according to the invention contain conventional excipients and diluents appropriate for the required mode of administration.
• pharmaceutical ancillary substances such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, liquid paraffin, petrolatum and wool fat.
• Suitable for internal use are, for example, lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone.
• antioxidants such as tocopherol and butylated hydroxyanisole as well as butylated hydroxytoluene, flavor-improving additives, stabilizers, emulsifiers and bleaches to be present.
• the substances present in the formulation in addition to the active substance, as well as the substances used to produce the pharmaceutical formulation must be toxicologically acceptable and compatible with the active substance in each case.
• the drug formulations are produced in a conventional way.
• Tablets of the following composition are compressed in a tableting machine in a conventional way:
• Aerosil® (chemically pure silica in sub-microscopically fine dispersion)
• Coated tablets of the following composition are produced in a conventional way:
• the core composition is composed of 9 parts of corn starch, 3 parts of lactose and 1 part of Luviskol® VA 64 (60:40 vinylpyrrolidone/vinyl acetate copolymer, cf. Pharm. Ind. 1962, 586).
• the sugar-coating composition is composed of 5 parts of sucrose, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The coated tablets produced in this way are subsequently provided with an enteric coating.

Landscapes

• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Epidemiology (AREA)
• Anesthesiology (AREA)
• Hospice & Palliative Care (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=6474850

Family Applications (1)

Country Status (13)

Citations (5)

• 1992
  • 1992-12-10 DE DE4241564A patent/DE4241564A1/de not_active Withdrawn
• 1993
  • 1993-12-06 AU AU56965/94A patent/AU673225B2/en not_active Ceased
  • 1993-12-06 AT AT94902687T patent/ATE177637T1/de not_active IP Right Cessation
  • 1993-12-06 CZ CZ951448A patent/CZ144895A3/cs unknown
  • 1993-12-06 EP EP94902687A patent/EP0673249B1/fr not_active Expired - Lifetime
  • 1993-12-06 DE DE59309469T patent/DE59309469D1/de not_active Expired - Fee Related
  • 1993-12-06 US US08/433,509 patent/US5612344A/en not_active Expired - Fee Related
  • 1993-12-06 KR KR1019950702355A patent/KR950703962A/ko not_active Application Discontinuation
  • 1993-12-06 JP JP6513758A patent/JPH08504418A/ja active Pending
  • 1993-12-06 NZ NZ258887A patent/NZ258887A/en unknown
  • 1993-12-06 CA CA002151241A patent/CA2151241A1/fr not_active Abandoned
  • 1993-12-06 WO PCT/EP1993/003424 patent/WO1994013294A1/fr active IP Right Grant
  • 1993-12-09 ZA ZA939229A patent/ZA939229B/xx unknown
  • 1993-12-10 MX MX9307837A patent/MX9307837A/es unknown

Patent Citations (6)

Non-Patent Citations (4)

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